EP0351987B1 - Verwendung von Polymeren bei einer Behandlung - Google Patents

Verwendung von Polymeren bei einer Behandlung Download PDF

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Publication number
EP0351987B1
EP0351987B1 EP89306864A EP89306864A EP0351987B1 EP 0351987 B1 EP0351987 B1 EP 0351987B1 EP 89306864 A EP89306864 A EP 89306864A EP 89306864 A EP89306864 A EP 89306864A EP 0351987 B1 EP0351987 B1 EP 0351987B1
Authority
EP
European Patent Office
Prior art keywords
carbomer
faecal
treatment
mucus
activity
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP89306864A
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English (en)
French (fr)
Other versions
EP0351987A1 (de
Inventor
John Gareth Lloyd-Jones
Peter William Dettmar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
COLMAN PRODUCTS Ltd
Reckitt Benckiser Healthcare UK Ltd
Original Assignee
Reckitt and Colman Products Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Reckitt and Colman Products Ltd filed Critical Reckitt and Colman Products Ltd
Priority to AT89306864T priority Critical patent/ATE80302T1/de
Publication of EP0351987A1 publication Critical patent/EP0351987A1/de
Application granted granted Critical
Publication of EP0351987B1 publication Critical patent/EP0351987B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/78—Polymers containing oxygen of acrylic acid or derivatives thereof

Definitions

  • This invention relates to the use of polyacrylates and in particular to carbomer, in the treatment of inflammatory bowel disease.
  • the polyacrylates are high molecular weight resins which may be linear or cross-linked. They find wide application as suspending agents in industries such as the oil, cosmetic and pharmaceutical industries.
  • Sodium polyacrylate has been suggested for use in the treatment of peptic ulcers.
  • British patent No 1435630 (Nippon Kayaku) describes a solid antipeptic ulcer composition comprising sodium polyacrylate having an intrinsic viscosity of 0.3 or more and a pharmaceutically inert solid carrier.
  • British patent No 1538352 (Nippon Kayaku) describes an improved composition which comprises granules of polyacrylic alkali metal salt coated with a water-insoluble but water permeable coating agent such as ethyl cellulose.
  • Suitable polyacrylic alkali metal salts are stated to include sodium polyacrylate of molecular weight 3000000 to 8000000. The only specific sodium polyacrylate mentioned is one of molecular weight about 3400000.
  • Carbomer is described in the British Pharmacopeia and the United States National Formulary as being a synthetic high molecular weight cross-linked polymer of acrylic acid containing 56 to 68% of carboxylic acid groups.
  • the British Pharmacopeia specifies cross-linking with allylsucrose.
  • US patent No 2909462 describes the use as a bulk laxative of a colloidally water-soluble polymer of acrylic acid cross-linked with from about 0.75% to 2.0% of polyallyl sucrose.
  • IBD Inflammatory bowel disease
  • Ulcerative colitis is a diffuse, non-specific, inflammatory disease of poorly understood aetiology. It is essentially a mucosal lesion which involves the rectum and which may extend for a variable length of the colon. Crohn's disease is an acute or chronic granulomatous disease which may affect any part of the alimentary tract but is mainly found in the terminal ileum, large intestine or both and is characterised by multiple lesions with normal intestine intervening between them. The breakdown of the colonic mucosal barrier and changes in colonic mucus secretion are features of IBD. As mucus is the only barrier between the epithelial cells and the colonic lumen, it is considered an important part of the protective mechanisms in IBD and increased degradation of the mucus layer would compromise mucosal defence.
  • Mucus secreted viscoelastic gel adheres to and covers the gastrointestinal mucosal surface protecting it against mechanical shear, micro-organisms and the action of allergens and toxins.
  • the mucus glyco-protein must retain its native polymeric structure [Allen, Trends in Biochemical Sciences, 8 (5), 169-173, 1983]. This is readily apparent following degradation of mucus gel, by proteolysis, to its glycoprotein subunits. These subunits have a lower intrinsic viscosity and provide a much weaker barrier.
  • enteric microflora The bacterial flora of the healthy gut is very stable and in symbiosis with the host. If this symbiotic relationship is disturbed, by for example altering the balance of the organisms, physical damage of the gut may result. Symptoms of inflammatory bowel disease are considered to be associated with bacterial overgrowth. [Hill, Current Concepts in Gastroenterology, 10 8-13 (4) 1985]. Inflammatory bowel disease is considered to be a two stage process, with an initiation and a maintenance phase. It is unclear whether the initiation phase of the disease is associated with microflora changes, however there is substantial evidence of bacterial involvement in the maintenance phase of the disease.
  • carbomer or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of inflammatory bowel disease.
  • the salt is the sodium salt.
  • the carbomer is carbomer 934P or its sodium salt.
  • the medicaments may be administered orally or rectally, as appropriate, according to the site of the disease.
  • US patent No 2909462 discloses the use of polyacrylates in the treatment of lower gastrointestinal disorders principally as laxatives.
  • therapeutic effectiveness of polyacrylates has been attributed to their ability to reduce water absorption by retaining water in the gut lumen. This action is entirely different to that described in the present invention and was not directed towards the treatment of ulcerative colitis or Crohn's disease.
  • the medicaments are for oral or rectal administration.
  • oral preparations they may be in the form of liquid compositions or solid compositions in the form of for example powders or granules, conveniently in unit dosage form in capsules or sachets.
  • rectal administration they may conveniently be in the form of aqueous retention enemas.
  • aqueous liquid compositions which are susceptible to contamination and subsequent deterioration by micro-organisms, it is preferable to include a preservative.
  • Suitable systems include combinations of methyl and propyl p-hydroxybenzoates (methyl parabens and propyl parabens).
  • Aqueous compositions containing neutralised carbomer at high concentration have a high viscosity which would render them unpourable.
  • the viscosity is reduced by increasing the ionic strength of the solution using suitable salts.
  • suitable salts which are acceptable biologically include bicarbonate salts of sodium and potassium, or citrate salts.
  • compositions of the present invention may also include one or more of a colouring, sweetening or flavouring agent.
  • the carbomer was dispersed, with agitation in about 75ml of water and aqueous sodium hydroxide wad added to give a final product pH of 7.5 to 8.0.
  • the sodium bicarbonate and methyl and propyl parabens were dispersed in 20ml of water and added to the carbomer gel. Additional water was added to make up to a final volume of 100ml followed by thorough mixing to produce a homogenous mixture.
  • Aqueous retention enemas can be produced with similar compositions to Examples (1) and (2)
  • Effective dispersion of the carbomer can be enhanced by the incorporation of disintegrating agents such as starch and its derivatives such as sodium starch glycollate and cellulose derivatives such as sodium carboxymethylcellulose and also by inclusion of effervescent combinations such as sodium bicarbonate - citric acid.
  • disintegrating agents such as starch and its derivatives such as sodium starch glycollate and cellulose derivatives such as sodium carboxymethylcellulose and also by inclusion of effervescent combinations such as sodium bicarbonate - citric acid.
  • Capsules were prepared from the following mixture.
  • Carbomer sodium salt was prepared by dispersing 1kg of carbomer in a solution of 400g sodium hydroxide in 3.6kg anhydrous methanol. The salt was collected by filtration, dried and comminuted.
  • the formulation ingredients were blended to produce a uniform mix and appropriate dose weights taken and filled into suitable size capsule shells.
  • Capsules soluble at pH7 and above were produced by coating the capsule of Examples 3 to 5 with a polymer which is resistant to acid conditions.
  • a suitable polymer is a polymethacrylate polymer Eudragit S (Rohm Pharma). This is an anionic polymer synthesised from methacrylic acid and methacrylic acid methyl ester; it is soluble at pH7 and above.
  • a solution suitable for capsule coating was prepared by dissolving the polymer in a suitable organic solvent eg ethanol, isopropanol or acetone.
  • the solvent may contain dissolved therein a plasticiser such as a polyethylene glycol, dibutyl phthalate, triacetin at a concentration of 10-25% of the polymer weight.
  • the concentration of polymer in the solvent was generally between 3 and 6% w/v.
  • the capsules were coated by suspending the capsules in a warm airstream and using a suitable spray gun to apply the coating solution until an acid impermeable coat thickness was achieved.
  • an effervescent base for example a citric acid/sodium bicarbonate mix.
  • Flavour, sweetening and colouring agents may also be included.
  • the ingredients were blended to produce a uniform mix which was filled into sachets.
  • Mucus gel scraped from the surface of pig or human colons was collected in a cocktail of proteinase inhibitors [1 .0mM phenylmethylsulphonyl fluoride (P.M.S.F), 50mM iodoacetamide, 100mM aminohexanoic acid, 5mM benzamidine HCl, 1.0 mg l ⁇ 1 soybean trypsin inhibitor and 10mM Na2E.D.T.A in 0.5M tris/HCl pH 8.0] [Hutton et al, Biochem. Soc. Trans. 15 (6), 1074 1987] and solubilised by mild homogenisation for 1 minute at full speed in a Waring blender.
  • P.M.S.F proteinase inhibitors
  • the solution viscosity of mucus glycoproteins and/or carbomer 934P was measured using a Contraves low shear cup and bob viscometer. Preparations of glycoprotein or polyacrylate were equilibrated with M/15M KH2PO4/Na2HPO4 pH 7.5 (containing 50mM NaCl) for 24 hours at 4°C before use.
  • Mucolytic activity was measured quantitatively by the increase in free peptide N-terminals formed by proteolytic cleavage of the mucus peptide core, as described in the methodology section referring to the in-vitro analysis of human faecal proteolytic activity.
  • Table 1 presents data illustrating the percentage synergistic increase in specific viscosity of pig colonic mucus glycoprotein - carbomer 934P mixtures above the calculated additive viscosities of the mucus glycoprotein and carbomer 934P measured separately at a carbomer 934P concentration of 2.0 mg ml ⁇ 1 at pH 7.5 and 25°C.
  • Table 2 presents data illustrating the percentage synergistic increase in specific viscosity of pig and human colonic mucus glycoprotein - carbomer 934P mixtures above the calculated additive viscosities of the mucus glycoprotein and carbomer 934P measured separately at a fixed mucus glycoprotein concentration of 1.0 mg ml ⁇ 1 at pH 7.5 and 25°C From Tables 1 and 2 it can be seen that carbomer 934P and mucus glycoprotein synergistically interact over a range of concentrations with colonic mucus. Similar interactions were observed for both pig and human colonic mucus.
  • the material was thoroughly dispersed in anaerobic Tris buffer (0.1M, pH7.0) containing 50mM mercaptoethanol to a final concentration of 10%.
  • Tris buffer 0.1M, pH7.0
  • the general protease substrate azocasein was used to determine faecal protolytic activity.
  • An aliquot of 0.5ml of a 10mg/ml solution of azocasein was added in triplicate to an equal volume of each faecal slurry.
  • Duplicate controls containing only substrate were set up and incubated simultaneously; the faecal slurry was added to these controls at the end of the incubation period.
  • the reaction was quenched after 1 hour at 37°C by the addition of 0.1ml of 50% trichloroacetic acid (TCA).
  • TCA trichloroacetic acid
  • Precipitated material was removed by centrifugation at 11400g for 5 mins. Supernatant (0.75ml) was added to an equal volume of 1.0M NaOH and the absorbance of the resultant solution determined in a spectrophotometer at 450nm. Extent of azocasein hydrolysis was determined from the intensity of TCA soluble coloured material and converted to concentration by a standard curve prepared from authentic azocasein. Specific protease activity in faeces was expressed as mg azocasein hydrolysed/hour/g wet weight faeces. The significance of the difference between protease activities and faecal outputs during periods 1 (control) and 2 (test) was determined using a students t-test. A treatment effect was considered significant if the p value was less than 0.05.
  • Table 3 presents test data showing effect of treatment with oral carbomer on rat faecal protease activity. Values presented are for 12 animals on placebo (control-treatment) and after 48 hours of carbomer (test-treatment)
  • Results presented in Table 3 demonstrate that treatment with oral carbomer significantly (p ⁇ 0.001) reduced faecal protease activity in rats. An overall decrease of 38% was attained. These data indicate that orally dosed carbomer enters the rat colon and is effective in reducing faecal protease activity.
  • Human faecal extracts (from asymptomatic volunteers) were obtained by suspending samples of stool in 4 volumes of M/15M KH2PO4/Na2HPO4 pH 7.5 containing 50mM NaCl and centrifuging at 10,000g for 15 minutes at 4°C. The supernatant was retained as the faecal extract.
  • Proteolytic activity was measured using a modification of the method of Lin et al., J.Biol.Chem. 244 (4), 789-793 (1969), i.e. a sensitive trinitrobenzene sulphonic acid assay for formation of new peptide N-terminals using succinyl albumin as substrate.
  • Faecal extract containing one unit of protease activity (equivalent to 1 ⁇ g trypsin) was mixed with 0.5ml buffer (M/15 phosphate pH7.5) or inhibitor.
  • Substrate 0.5ml, 8 mg ml ⁇ 1 succinyl albumin
  • Table 4 presents data illustrating the % inhibition of faecal proteolytic activity by a range of concentrations of carbomer 934P at pH 7.5 and 37°C. From Table 4 it can be seen that carbomer 934P over the range of concentrations 2.0 - 0.12 mg ml ⁇ 1 significantly inhibited colonic proteolytic activity.
  • Table 5 presents data illustrating the effect of carbomer 934P compared with a range of other polymers on faecal proteolytic activity at pH 7.5 and 37°C. From Table 5 it can be seen that carbomer 934P possesses superior inhibition of faecal proteolytic activity when compared to a range of other polymers.
  • Table 6 shows the percentage inhibition of mucolysis achieved at pH 7.5 and 37°C by varying concentrations of carbomer 934P in the presence of one unit of faecal protease activity (equivalent to 1 ⁇ g trypsin), 15 minute incubation time. From Table 6 it can be seen that carbomer 934P inhibits proteolytic mucolysis in a dose related manner.
  • the slurry was then fractionated into a washed bacterial cell fraction (WCF), a washed particulate fraction (WPF) and a supernatant fraction (SFF) by multistep centrifugation according to the scheme:
  • WCF washed bacterial cell fraction
  • WPF washed particulate fraction
  • SFF supernatant fraction
  • the fractions were diluted in an equal volume of anaerobic buffer and assayed for general protease activity using azocasein as substrate as described above.
  • Concurrently each fraction from each sample was assayed for trypsin-like activity using benzoyl-arginine p-nitroanilide (BAPNA) by a modification of the method of Appel: Methods in Enzymatic Analysis, 2nd Edn., Vol 2, pp949-974, (1984).
  • a 1.2mM solution of BAPNA was prepared in anaerobic Tris buffer and added in triplicate to an equal volume (0.5ml) of faecal material.
  • Control assays were performed in duplicate by incubation of substrate only. These mixtures were incubated at 37°C for 1 hour at which time the faecal fractions were added to control tubes and all reactions stopped by the addition of 0.1ml of 50% TCA. Particulate and precipitated material was removed by centrifugation at 11400g for 5 mins. Aliquots (0.75ml) of the supernatant were added to 0.75ml ice-cold sodium nitrite solution (1.0mg/ml) in fresh tubes.
  • Table 7 presents test data describing the effect of oral carbomer on human faecal trypsin-like activity as shown by BAPNA hydrolysis (Table 7a) and on general protease activity as shown by azocasein hydrolysis (Table 7b).
  • the proteolytic activity in human faecal samples normally falls within the range of 30 to 300 ⁇ g g ⁇ 1, expressed as ⁇ g trypsin equivalents per g wet weight of stool. It is envisaged that the inhibition of the proteolytic activity in human stools (average daily stool 150g wet weight) will be achieved following the administration of carbomer in the range 200mg to 3g per unit dose. The dose selected will be dependent on whether the treatment is for the maintenance of patients during the remission phase of active inflammatory bowel disease or whether used as a treatment therapy during the relapse phase of the disease when elevated levels of proteolytic activity are observed.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Graft Or Block Polymers (AREA)
  • Chemical Treatment Of Metals (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Claims (4)

  1. Verwendung von Carbomer oder einem pharmazeutisch verträglichen Salz davon als das einzige aktive Mittel zur Herstellung eines Medikaments zur Behandlung von entzündlicher Darmkrankheit.
  2. Verwendung nach Anspruch 1,
    dadurch gekennzeichnet , daß
    das pharmazeutisch verträgliche Salz das Natriumsalz ist.
  3. Verwendung nach Anspruch 1,
    dadurch gekennzeichnet , daß
    das Carbomer Carbomer 934P oder sein Natriumsalz ist.
  4. Verwendung nach einem der Ansprüche 1 bis 3,
    dadurch gekennzeichnet , daß
    das Medikament in Form einer Einheitsdosis ist und von 200mg bis 3g des Carbomers pro Einheitsdosis enthält.
EP89306864A 1988-07-16 1989-07-06 Verwendung von Polymeren bei einer Behandlung Expired - Lifetime EP0351987B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT89306864T ATE80302T1 (de) 1988-07-16 1989-07-06 Verwendung von polymeren bei einer behandlung.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8817015 1988-07-16
GB888817015A GB8817015D0 (en) 1988-07-16 1988-07-16 Method of treatment

Publications (2)

Publication Number Publication Date
EP0351987A1 EP0351987A1 (de) 1990-01-24
EP0351987B1 true EP0351987B1 (de) 1992-09-09

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EP89306864A Expired - Lifetime EP0351987B1 (de) 1988-07-16 1989-07-06 Verwendung von Polymeren bei einer Behandlung

Country Status (8)

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US (1) US5051253A (de)
EP (1) EP0351987B1 (de)
AT (1) ATE80302T1 (de)
DE (1) DE68902798T2 (de)
DK (1) DK349889A (de)
GB (2) GB8817015D0 (de)
IE (1) IE61314B1 (de)
ZA (1) ZA895256B (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10695363B2 (en) 2017-04-14 2020-06-30 Gelesis Llc Compositions and methods for treating or preventing gut permeability-related disorders

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KR100193933B1 (ko) * 1990-07-20 1999-06-15 에밀리오 캠포레시, 존 페르구손 비스무트와 폴리아크릴레이트와의 수용성 착체, 이의 제조 방법 및 상기 착체 또는 다른 비스무트염을 함유하는 궤양성 대장염 치료용 약제학적 조성물
JPH05186357A (ja) * 1991-12-31 1993-07-27 Shigeo Ochi 飲食物消化分解産物吸収抑制手段
DE19619238A1 (de) * 1996-05-13 1997-11-20 Hoechst Ag Antiadhäsive Eigenschaften von Polyacrylsäuren und Polymethacrylsäuren
GB9623962D0 (en) * 1996-11-15 1997-01-08 Tillotts Pharma Ag Pharmaceutical composition
JP2004517066A (ja) * 2000-11-20 2004-06-10 ダウ グローバル テクノロジーズ インコーポレイティド 水吸収性ポリマーの生体内での使用
EP1847271A3 (de) * 2000-11-20 2008-08-06 Sorbent Therapeutics, Inc. Wasser-absorbierende Polymere und ihre Verwendung als Arzneimittel
US8263112B2 (en) * 2000-11-20 2012-09-11 Sorbent Therapeutics, Inc. In vivo use of water absorbent polymers
CH697081A5 (de) * 2002-01-22 2008-04-30 Andreas F Dr Schaub Zusammensetzung für die Unterstützung der Geburt eines menschlichen Föten.
KR101228233B1 (ko) 2004-03-30 2013-01-31 리립사, 인크. 이온 결합 중합체 및 이의 용도
US7556799B2 (en) * 2004-03-30 2009-07-07 Relypsa, Inc. Ion binding polymers and uses thereof
US7854924B2 (en) * 2004-03-30 2010-12-21 Relypsa, Inc. Methods and compositions for treatment of ion imbalances
US7429394B2 (en) * 2004-03-30 2008-09-30 Relypsa, Inc. Ion binding compositions
US8282960B2 (en) * 2004-03-30 2012-10-09 Relypsa, Inc. Ion binding compositions
US8192758B2 (en) * 2004-03-30 2012-06-05 Relypsa, Inc. Ion binding compositions
DE102004054552A1 (de) * 2004-11-11 2006-05-18 Hcb Happy Child Birth Holding Ag Neue Zusammensetzung zur Erleichterung der Humangeburt
AU2006294455B2 (en) * 2005-09-30 2013-06-20 Relypsa, Inc. Methods for preparing core-shell composites having cross-linked shells and core-shell composites resulting therefrom
DE112006002618T5 (de) 2005-09-30 2008-08-28 Ilypsa Inc., Santa Clara Verfahren und Zusammensetzungen zum selektiven Entfernen von Kaliumionen aus dem Gastrointestinaltrakt eines Säugers
FI3431094T3 (fi) * 2008-08-22 2023-03-20 Vifor Int Ltd Silloitettuja kationinvaihtopolymeerejä, koostumuksia ja käyttö hyperkalemian hoidossa
US20100104527A1 (en) * 2008-08-22 2010-04-29 Relypsa, Inc. Treating hyperkalemia with crosslinked cation exchange polymers of improved physical properties
WO2010022380A2 (en) 2008-08-22 2010-02-25 Relypsa, Inc. Linear polyol stabilized polyfluoroacrylate compositions
BR112015007749A2 (pt) 2012-10-08 2017-07-04 Relypsa Inc métodos para tratamento de hipertensão , de hipercaliemia , e de doença renal crônica.

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BE635819A (de) * 1962-08-06
FR2221139B1 (de) * 1973-03-13 1978-03-24 Nippon Kayaku Kk
US3930005A (en) * 1973-06-15 1975-12-30 Squibb & Sons Inc Antiinflammatory agents and their use
SE7504049L (sv) * 1975-04-09 1976-10-10 Haessle Ab Colonpreparation
JPS52139715A (en) * 1976-05-14 1977-11-21 Nippon Kayaku Co Ltd Coated granules of alkali polyacrylate
GB1567889A (en) * 1977-04-12 1980-05-21 Nippon Kayaku Kk Orally administrable anti-tumour compositions for enhancing absorption of antitumour agent into a gastrointestinal tomour site
JPS59163310A (ja) * 1983-03-07 1984-09-14 Kyoto Yakuhin Kogyo Kk 直腸投与用組成物
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10695363B2 (en) 2017-04-14 2020-06-30 Gelesis Llc Compositions and methods for treating or preventing gut permeability-related disorders

Also Published As

Publication number Publication date
GB2220855B (en) 1992-01-22
DK349889D0 (da) 1989-07-14
EP0351987A1 (de) 1990-01-24
US5051253A (en) 1991-09-24
DE68902798D1 (de) 1992-10-15
DK349889A (da) 1990-01-17
IE892285L (en) 1990-01-16
ZA895256B (en) 1990-04-25
GB2220855A (en) 1990-01-24
GB8817015D0 (en) 1988-08-17
DE68902798T2 (de) 1993-01-14
GB8915834D0 (en) 1989-08-31
ATE80302T1 (de) 1992-09-15
IE61314B1 (en) 1994-10-19

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